Month: September 2013

Remember those exam questions in organic chemistry where you were asked to design the synthesis of a compound starting with a simple organic molecule? Some saw “organic” as a hurdle on the way to biochemistry in medical school; others stayed the course and kept developing new syntheses. A very long and very detailed article in Science (23 August 2013) describes the short and inexpensive synthesis of (+) –ingenol — the basis of a new FDA-approved compound for treating actinic keratosis (ingenol mebutate). Before, the only source of the molecule was through relatively inefficient procedures starting with Euphorbia peplus. The details of the procedure will interest chemistry aficionados; for me, there were two more general messages:

First: natural compounds — even those that seem, and are, very complex — can be synthesized using today’s techniques. (Jorgensen et al describe a 14-step synthesis with an overall yield of 1.2%, which compares favorably with ingenol’s isolation from natural materials.)

Second: as impressive to me was that LEO Pharma supported this research in conjunction with the Department of Chemistry at Scripps, evidence of very creative interactions between industry and academia and an important model for many kinds of research.

This section is for advanced credit.The official name of Euphorbia peplus is Euphorbia peplus L. The L. means that the ultimate authority, Carolus Linneaeus, named the species. See http://www.plants.usda.gov for some details and pictures of the plant called the “petty spurge”. The plant has other names such as ‘cancer weed’ and ‘radium weed’. The origin of those names, especially the latter,deserves some further documentation since the word “radium” did not exist until 1898. If there are botany namers reading this, their responses are welcomed.

Lymphatics were a challenge to me and my fellow medical students during our gross anatomy class a half century ago. We could find arteries and veins galore, but where were the elusive lymphatics? Even the two larger connections between the venous and lymphatic systems were elusive.

Lymphatic biology has progressed exponentially since then. For two days in May, 2013 the world’s lymphatic gurus gathered at Yale to fete the rich molecular biology and physiology of the lymphatics, as summarized recently in Science (Simons and Eichmann, 2013). As of August 17, 2013, lymphedema was a feature of almost 70 genetic diseases and syndromes in OMIM, and many common conditions are transmitted by — or alter — lymphatics. Vascular endothelial growth factors and their receptors are major players in lymphatic development, and an RNA binding protein antigen, R(huR), and other molecules are important VEGF modulators. Lymphatics continue to be the subject of many narratives, with implications for cutaneous biology and cutaneous diseases, both inflammatory and neoplastic. The key role of lymphatic endothelial cells during the transit of dendritic cells from the periphery to lymph nodes is highlighted in the September issue of JID, underscoring the importance of lymphatics in cutaneous inflammatory biology. (Teijeira et al, 2013)

I started with history and end on a historical theme. Dermatology and Yale have a rich history in lymphatic and vascular biology, and Irwin Braverman, currently a Professor of Dermatology at Yale, published a masterful review in 1983 on the role of blood vessels and lymphatics in skin diseases containing many of his seminal original studies.(Braverman, 1983) I suspect he is pleased that skin and lymphatics are still closely intertwined and that Yale was the setting for this vascular biology meeting.